Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 12th North Avenue, Sherbrooke, Canada.
Sherbrooke Molecular Imaging Center, Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, 3001 12th North Avenue, Sherbrooke, Canada.
Nucl Med Biol. 2018 Jan;56:31-38. doi: 10.1016/j.nucmedbio.2017.10.006. Epub 2017 Oct 23.
Gastrin releasing peptide receptors (GRPRs) are significantly over-expressed on a large proportion of prostate cancers making them prime candidates for receptor-mediated nuclear imaging by PET. Recently, we synthesized a novel bifunctional chelator (BFC) bearing hydroxamic acid arms (DOTHA). Here we investigated the potential of a novel DOTHA-conjugated, Cu-radiolabeled GRPR peptide antagonist, [D-Phe-Sta-Leu-NH]bombesin(6-14) (DOTHA-PEG-RM26) to visualize prostate tumors by PET imaging.
DOTHA-PEG-RM26 was conveniently and efficiently assembled on solid support. The compound was radiolabeled with Cu and its affinity, stability, cellular uptake on PC3 prostate cancer cells were evaluated. The in vitro and in vivo behavior of [Cu]DOTHA-PEG-RM26 was examined by PET imaging using human PC3 prostate cancer xenografts and its behavior was compared to that of the analogous [Cu]NOTA-PEG-RM26.
The inhibition constant of Cu-DOTHA-PEG-RM26 was in the low nanomolar range (0.68±0.19 nM). The [Cu]DOTHA-PEG-RM26 conjugate was prepared with a labeling yield >95% and molar activity of 56±3 GBq/μmol after a 5-min room temperature labeling. [Cu]-DOTHA-PEG-RM26 demonstrated rapid blood and renal clearance as well as a high tumor uptake. Small animal PET images confirmed high and specific uptake in PC3 tumor. Both [Cu]-DOTHA-PEG-RM26 and [Cu]-NOTA-PEG-RM26 displayed similar tumor and normal tissue uptakes at early time point post injection.
[Cu]-DOTHA-PEG-RM26 allows visualization of prostate tumors by PET imaging. DOTHA enables fast Cu chelation under mild condition, and as such could be used advantageously for the development of other Cu-labeled peptide-derived PET tracers.
胃泌素释放肽受体（GRPRs）在很大一部分前列腺癌中过度表达，使其成为通过 PET 进行受体介导的核成像的首选候选者。最近，我们合成了一种带有羟肟酸臂的新型双功能螯合剂（BFC）（DOTHA）。在这里，我们研究了一种新型的 DOTHA 缀合的、Cu 放射性标记的 GRPR 肽拮抗剂，[D-Phe-Sta-Leu-NH] bombesin（6-14）（DOTHA-PEG-RM26）通过 PET 成像可视化前列腺肿瘤的潜力。
DOTHA-PEG-RM26 在固体载体上方便有效地组装。该化合物用 Cu 标记，并评估其亲和力、稳定性、对 PC3 前列腺癌细胞的细胞摄取。通过人 PC3 前列腺癌异种移植的 PET 成像研究了[Cu]DOTHA-PEG-RM26 的体外和体内行为，并将其与类似的[Cu]NOTA-PEG-RM26 的行为进行了比较。
Cu-DOTHA-PEG-RM26 的抑制常数为低纳摩尔范围（0.68±0.19 nM）。[Cu]DOTHA-PEG-RM26 缀合物的标记产率>95%，室温下标记 5 分钟后摩尔活性为 56±3GBq/μmol。[Cu]-DOTHA-PEG-RM26 表现出快速的血液和肾脏清除以及高肿瘤摄取。小动物 PET 图像证实了 PC3 肿瘤的高特异性摄取。在注射后早期，[Cu]-DOTHA-PEG-RM26 和[Cu]-NOTA-PEG-RM26 均显示出类似的肿瘤和正常组织摄取。
[Cu]-DOTHA-PEG-RM26 通过 PET 成像允许可视化前列腺肿瘤。DOTHA 能够在温和条件下快速螯合 Cu，因此可用于开发其他 Cu 标记的肽衍生的 PET 示踪剂。
